[go: up one dir, main page]

WO1995027701A1 - Mimes steroides contenant un metal et ligands utiles dans la preparation desdits mimes - Google Patents

Mimes steroides contenant un metal et ligands utiles dans la preparation desdits mimes Download PDF

Info

Publication number
WO1995027701A1
WO1995027701A1 PCT/US1995/004338 US9504338W WO9527701A1 WO 1995027701 A1 WO1995027701 A1 WO 1995027701A1 US 9504338 W US9504338 W US 9504338W WO 9527701 A1 WO9527701 A1 WO 9527701A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
composition
hydroxyalkyl
alkyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1995/004338
Other languages
English (en)
Inventor
Raghavan Rajagopalan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mallinckrodt Inc
Original Assignee
Mallinckrodt Medical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mallinckrodt Medical Inc filed Critical Mallinckrodt Medical Inc
Priority to JP7526470A priority Critical patent/JPH09512251A/ja
Priority to EP95916251A priority patent/EP0754177A4/fr
Publication of WO1995027701A1 publication Critical patent/WO1995027701A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0493—Steroids, e.g. cholesterol, testosterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention relates in general to metal- containing compositions which mimic the skeletal structure of a steroid, and more particularly to such compositions in which a selected metal ion is integrated into a tertiary or quaternary center of a steroid skeleton structure by occupying a position in the steroid structure previously occupied by a carbon atom and which are useful in delivering a metal to a targeted site for diagnostic or therapeutic purposes.
  • Radiopharmaceuticals capable of delivering a selected metal ion to a targeted biological site has been the focus of much research in the biological and medical fields. Radiopharmaceuticals have, in fact, been developed that are capable of being targeted to a specific site and have found use in radioimaging, radiotherapy, and as a tool for the prognosis of disease. In recent years the use of radiopharmaceuticals to diagnose, image and/or provide therapy for tumors has been increasing. Recent studies have also shown that steroid receptors in tumor cells, such as those found in breast cancer and prostate cancer, may provide important prognostic, information on the status of the tumor and in selecting an effective course of treatment. Rayter, Z., "Steroid Receptors in breast cancer, " Br. J. Sur ⁇ .
  • steroid receptors on tumors or other biological tissues could be utilized would be to attach a radiolabelled metal complex to the steroid molecule which binds to the receptor.
  • Various effector molecules such as drugs, enzymes, chemotoxins, probes, and the like, have been prepared for targeted delivery to a biological site by covalently attaching a receptor specific carrier molecule, such as an antibody or a peptide, thereto. Halpern et al., Diagnostic Imaging, 1983, 40; Hnatowich et al. , Science, 1983, 220, 613. This approach has been referred to as an "external bifunctional" approach and has found some success.
  • the carrier is a small molecule, i.e. one having a molecular weight of less than about 500 Daltons, the attachment of effector molecules often destroys the receptor binding capability of the carrier molecule.
  • Steroids are small molecules, typically having a molecular weight of around 400 Daltons, and the covalent attachment of a radioactive metal complex to the steroid may obstruct the ability of the steroid to bind to the receptor.
  • any steroid based radiopharmaceutical should be one that does not adversely affect the binding properties of the steroid.
  • an effective steroid-based radiopharmaceutical should maintain the relative size, shape and structure of the steroid molecule.
  • the present invention is directed to a composition comprising a metal ion incorporated into a steroid skeleton structure and ligands useful in the preparation of such compositions.
  • a composition comprised of a steroid skeleton structure having a metal ion at at least one of the tertiary or quaternary centers of the steroid skeleton structure and a donor atom capable of bonding to the metal ion at the positions in the steroid skeleton structure which are adjacent to the metal ion is provided.
  • the metal ion is preferably a radionuclide useful in radioimaging or radiotherapy.
  • the radionuclide is incorporated directly into the molecular framework of the steroid molecule in such a manner that the resulting composition is similar in size, shape and molecular topology to a non-modified steroid and retains the relative binding properties of a steroid molecule.
  • the present invention is further directed to ligands useful in preparing radionuclide compositions having the structure:
  • R 1 and R 2 are the same or different and each is selected from the group consisting of hydrogen, hydroxyl, carboxyl, amino, alkyl, aryl, alkaryl, alkaroyl, hydroxyalkyl, hydroxyalkaroyl, alkoxy, alkoxycarbonyl and carbamoyl and where the carbon containing portions contain between 1 and 10 carbon atoms;
  • R 3 , R 4 and R 5 are the same or different and each is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl or mercaptoalkyl and where the carbon containing portions contain between 1 and 6 carbon atoms;
  • Y 1 is selected from the group consisting of -SH, or -NR 6 R 7 , R 6 and R 7 being the same or different and are defined in the same manner as R 1 and R 3 , respectively;
  • R 8 and R 9 are the same or different and each is selected from the group consisting of hydrogen, hydroxyl, carboxyl, amino, alkyl, aryl, alkaryl, alkaroyl, hydroxyalkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl and carbamoyl and where the carbon containing portions contain between 1 and 10 carbon atoms;
  • R 10 , R 11 , and R 12 are the same or different and each is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl or mercaptoalkyl and where the carbon containing portions contain between 1 and 6 carbon atoms;
  • X 2 is selected from the group consisting of -SH and -NR 13 R 14 , R 13 and R 14 being the same or different and are defined in the same manner as R 8 and R 10 , respectively; and
  • the present invention is also directed to metal radionuclide complexes having the structure:
  • R 15 and R 16 are the same or different and each is selected from the group consisting of hydrogen, hydroxyl, carboxyl, amino, alkyl, aryl, alkaryl, alkaroyl, hydroxyalkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl and carbamoyl and where the carbon containing portions contain between 1 and 10 carbon atoms;
  • > ⁇ is selected from the group consisting of hydrogen, alkyl, aryl, alkaryl, hydroxyalkyl, mercaptoalkyl, and alkoxyalkyl;
  • R 18 and R 19 are the same or different and each is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl or mercaptoalkyl and where the carbon containing portions contain between 1 and 6 carbon atoms;
  • Y 3 is selected from the group consisting of -S- and -NR 20 R 21 , where R 20 and R 21 are defined in the same manner as R 15 and R 18 , respectively;
  • M 1 is selected from the group consisting of Technetium, Rhenium, Indium, Gallium, Cobalt, Copper, Yttrium, Terbium, Samarium, Holmium, Lutetium, Gadolinium, Manganese and Iron;
  • radionuclide complex having the structure:
  • R 22 and R 23 are the same or different and each is selected from the group consisting of hydrogen, hydroxyl, carboxyl, amino, alkyl, aryl, alkaryl, alkaroyl, hydroxyalkyl, hydroxyalkaryl, alkoxy, alkoxycarbonyl and carbamoyl and where the carbon containing portions contain between 1 and 10 carbon atoms;
  • R 25 is selected from the group consisting of hydrogen, alkyl, aryl, alkaryl, hydroxyalkyl and alkoxyalkyl;
  • R 26 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl or mercaptoalkyl and where the carbon containing portions contain between 1 and 6 carbon atoms;
  • Y 4 is selected from the group consisting of -SH, or -NR 7 R 28 ,
  • R 27 and R 28 being the same or different and are defined in the same manner as R 21 and R 26 , respectively, and
  • M 2 is selected from the group consisting of Technetium, Rhenium, Indium, Gallium, Cobalt, Copper, Yttrium, Terbium, Samarium, Holmium, Lutetium, Gadolinium, Manganese and Iron;
  • R 29 and R 30 are the same or different and each is selected from the group consisting of hydrogen, hydroxyl, carboxyl, amino, alkyl, aryl, alkaryl, alkaroyl, hydroxyalkyl, hydroxyalkaryl, alkoxy, alkoxycarbonyl and carbamoyl and where the carbon containing portions contain between 1 and 10 carbon atoms;
  • R 31 and R 32 are selected from the group consisting of hydrogen, alkyl, aryl, alkaryl, hydroxyalkyl and alkoxyalkyl;
  • R 33 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl or mercaptoalkyl and where the carbon containing portions contain between 1 and 6 carbon atoms;
  • Y 5 is selected from the group consisting of -SH, or -NR 34 R 3B ,
  • R 34 and R 35 being the same or different and are defined in the same manner as R 29 and R 32 , respectively.
  • M 3 is selected from the group consisting of Technetium, Rhenium, Indium, Gallium, Cobalt, Copper, Yttrium, Terbium, Samarium, Holmium, Lutetium, Gadolinium, Manganese and Iron, and
  • R 36 and R 37 are the same or different and each is selected from the group consisting of hydrogen, hydroxyl, carboxyl, amino, alkyl, aryl, alkaryl, alkaroyl, hydroxyalkyl, hydroxyalkaryl, alkoxy, alkoxycarbonyl and carbamoyl and where the carbon containing portions contain between 1 and 10 carbon atoms;
  • R 38 and R 39 are selected from the group consisting of hydrogen, alkyl, aryl, alkaryl, hydroxyalkyl and alkoxyalkyl;
  • R 40 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl or mercaptoalkyl and where the carbon containing portions contain between 1 and 6 carbon atoms;
  • Y 6 is selected from the group consisting of -SH, or -NR 1 R 42 , R 41 and R 42 being the same or different and are defined in the same manner as R 36 and R 40 , respectively.
  • M 4 is selected from the group consisting of Technetium, Rhenium, Indium, Gallium, Cobalt, Copper, Yttrium, Terbium, Samarium, Holmium, Lutetium, Gadolinium, Manganese and Iron, and
  • Also provided by the present invention is a method of using the radionuclide complex composition of the present invention by administering it to an individual, in a pharmacologically acceptable carrier, for imaging, diagnostic, or therapeutic purposes.
  • the diagnostic method permits detecting the presence or absence of a biological tissue that has a particular steroid receptor associated therewith by administering a diagnostically effective amount of the radionuclide complex to an individual.
  • the therapeutic method permits the delivery of a therapeutic amount of the radionuclide complex to a biological site that has a particular steroid receptor associated therewith by administering the complex to an individual.
  • a radionuclide complex that mimics the molecular topology of a steroid molecule; a radionuclide complex that is capable of binding to a steroid receptor in a manner similar to a natural steroid molecule; a steroid-based radionuclide complex that is of a size to permit it to permeate cell and nuclear membranes so as to bind to steroid receptors in the nucleus of a cell; and a method for imaging or providing therapy to biological tissue containing steroid receptors utilizing a radionuclide-steroid complex.
  • this internal bifunctional approach can be utilized to place a phosphorous atom at any site in the steroid skeleton.
  • the adjacent atoms can be either carbon or heteroatoms such as oxygen, sulfur, or nitrogen.
  • FIGS. 1 and 2 depict chemical synthesis protocols that may be used to prepare certain compounds of the present invention. Detailed Description of the Preferred Embodiments
  • At least one of the tetrahedral carbon centers of a steroid skeleton structure may be replaced by a metal ion provided that the adjacent centers are replaced by a suitable donor atom capable of bonding to a metal ion to provide a radionuclide complex.
  • the metal ion can assume a tetrahedral or square-pyramidal geometry. In this manner, a radionuclide complex that mimics the steroid structure in molecular topology, size, and binding properties is provided.
  • radionuclide-steroid mimics may be provided which, upon complexation with the appropriate metal under the appropriate complexing conditions, form the radionuclide- steroid mimic compositions of this invention.
  • radionuclide complexes that mimic the steroid perhydrocyclopentanophenanthrene ring structure (the steroid skeleton structure) are provided that have physical and biological characteristics, such as molecular topology, size and binding properties, that are similar to those of a non-modified steroid molecule.
  • Radionuclides prepared in accordance with the present invention can be used as radioimaging agents, radiotherapeutic agents, or as prognostication tools for analysis of disease states. It is known that steroid receptors are found in some tumor cells, particularly breast cancer and prostate cancer cells, and that an association between the presence of steroid receptors and the cancer exists. As a result, the radionuclide steroid mimics of the present invention find particular use in radioimaging, radiotherapy or as an aid in the prognostication of the state of a tumor or other biological tissue that has steroid receptors associated therewith. It is believed that the steroid-based radionuclides or "mimics" are likely to provide more consistent results because of the similarity of the structure to the natural steroid molecule and the increased likelihood that specific binding will occur.
  • a typical steroid molecule consists of a perhydrocyclopentanophenanthrene ring structure and may be either an aliphatic or an aromatic steroid.
  • These general structures are hereinafter referred to as the "steroid skeleton structure" and are illustrated below as structures VII and VIII, respectively:
  • the carbon centers at positions 5, 8, 9, 14, and 17 in structure VII, and the carbon centers at positions 8, 9, 14 and 17 in structure VIII are regarded as tertiary centers and the carbon centers at positions 10 and 13 in structure VII and position 13 in structure VIII are regarded as quaternary centers.
  • a selected metal ion is positioned at one of the tertiary or quaternary centers of the steroid structure and donor atoms, heteroatoms capable of bonding to the metal ion, are positioned at the carbon centers adjacent to the position located by the metal ion in place of the carbon atoms.
  • the donor atoms preferably contain a thiol, amide, carboxylate or an amine group.
  • the donor atoms adjacent to the selected position of the metal ion will provide an N 3 S or N 2 S 2 chelating core in order to satisfy the valency of the metal ion like technetium, rhenium, and gallium. It is also possible to incorporate the metal ions at the secondary centers in the steroid skeleton, but it is preferred to utilize the tertiary and quaternary centers.
  • the radionuclide complex of the present invention will have one of the following schematic structures (IX-XIX) :
  • M is a metal ion and X, Y and W are donor atoms capable of bonding to the metal ion and forming a radionuclide complex.
  • X, Y and W are donor atoms capable of bonding to the metal ion and forming a radionuclide complex.
  • other reactive moieties or ligands may be required to satisfy the valency of the metal ion in the above schematic structures to provide a stable metal complex and that various sidechains may be presented at any of the remaining carbon centers of the steroid skeleton for particular steroid structures.
  • the steroid mimic ligands described above provide four donor atoms and for metals having additional sites, these could be filled by water, hydroxide, chloride atoms or other ligands.
  • the metal ion incorporated into the steroid skeleton structure can be any metal ion that is useful in therapy, imaging, or for the prognosis of disease.
  • radioactive isotopes of metals are used for diagnostic imaging, and therapeutic applications, but non- radioactive metal ions can be used for MRI and X-ray diagnostic procedures.
  • useful radionuclide metals include, but are not limited to gamma-emitting nuclides such as, Tc-99m, In-Ill, Tl-201, Co-57, Cu-67; Ga-67 and Re-186.
  • Useful therapeutic radionuclide metals include, but are not limited to beta and/or alpha emitting nuclides such as, Yt- 90, Sr-89, Sm-153, Ho-166, Re-186, Re-188, Pb-212 and Tb- 161.
  • Useful diagnostic metals for MRI and/or X-ray contrast media include, but ar not limited to Gd, Mn, Fe, Dy, Bi, W and Pb.
  • a list of radionuclides can be found in the text "Table of Isotopes, " Seventh Edition (ed. Lederer and Shirley, John Wiley and Sons, Inc.) the entirety of which is herein incorporated by reference hereto.
  • Ligands useful in the preparation of the radionuclide complexes of this invention are prepared as a precursor to the radionuclide complexes and are useful compositions.
  • the ligands are useful in the preparation of the radionuclide complexes in that the ligand is typically provided separate from the radionuclide for commercial use. Therefore, the ligands of this invention are useful as a component of kits for producing radionuclide complexes.
  • the radionuclide containing solution may be obtained from radionuclide generators in a known manner. For example, when forming a technetium complex, a pertechnate solution may be obtained from a technetium generator in a known manner.
  • the radionuclide complex forming reaction is then carried out under appropriate reaction conditions.
  • the technetium 99m complex forming reaction is carried out under technetium complex forming temperatures, e.g. 20C to about 100C for 10 minutes to several hours.
  • An excess of the appropriate ligand over the radionuclide complex forming amounts is generally used.
  • ligands of the following structures (I, II, XXV - XXVII)
  • radionuclide complexes having one of the structures IX - XIX, as shown above.
  • the formation of radionuclide complexes is well known to those skilled in
  • FIG. 1 A schematic diagram of the synthesis of two exemplary N 2 S 2 and N 3 S metal based steroid mimics are shown in Figures 1 and 2, respectively.
  • the starting materials i.e. compounds 1, 3, 6 and 8 can be prepared by standard 0 functional group transformations from commercially available chemicals, i.e. 3-methoxyphenethylamine, 3- hydroxyphenylalanine, 2,3-dimercapotopropanol, and mercaptoethylamine.
  • Preparation of the dihydroisoquinoline derivatives 2 or 7 is accomplished via the known Bischler- Napieralski reaction (T.R. Govindachari et al., Organic Reactions, Volume 6) .
  • the tetrahydroisoguioline derivatives can be prepared by the Pictet-Spengler procedure using appropriate ⁇ - phenethylamine derivatives and aldehydes.
  • the key step in the synthesis is the alkylation of the amines 3 or 8 with the bromides 2 or 7. Subsequent steps are routine and standard functional group transformations.
  • R 1 is -OH or -OCH 3 ;
  • R 2 is -H or -COCH 3 ;
  • R 3 is -CH 3 ;
  • R 4 is -CH 2 SH;
  • R 5 is -H;
  • Y 1 is -SH or -NHCOCH 3 .
  • R 8 is -OH or -OCH 3 ;
  • R 9 is -H or
  • R 15 is -OH or -OCH 3 ;
  • R 16 is -H or -COCH 3 ;
  • R 17 is -CH 3 ;
  • R 18 is -CH 2 S-;
  • R 19 is -H;
  • Y 3 is -S " or
  • R 22 is -OH or -OCH 3 ;
  • R 23 is -H or -COCH 3 ;
  • R 24 is -CH 3 ;
  • R 25 and R 26 are -H;
  • X 4 is -CH 2 S " ;
  • Y 4 is -S " or -NCOCH 3 .
  • R 29 is -OH or -OCH 3 ;
  • R 30 is -H or -COCH 3 ;
  • R 31 is -CH 3 ;
  • R 32 is -CH 2 S " ;
  • R 33 is -H;
  • Y 5 is -S " or -NCOCH 3 ;
  • R 36 is -OH or -OCH 3 ;
  • R 37 is -H or -C0CH 3 ;
  • R 38 is -CH 3 ;
  • R 39 and R 40 are -H;
  • X 6 is -CH 2 S " ;
  • Y 6 is -S' or -NCOCH 3 ;
  • the labelling of ligands can be accomplished even with the protecting groups intact. It is known that thioketals and hemithioketals are cleaved under acidic conditions using heavy metal ions such as mercury or silver (T. Greene, Protective Groups in Organic Synthesis, J. Wiley: New York, 1991) . It has been shown that the S- tetrahydropyranyl(s-THP) group containing N 3 S ligands undergo efficient labelling with Tc and Re without prior removal of the protecting group (Srinivasan, et al. , U.S. Patent No. 5,021,556). It has also been demonstrated that the S-THP group is efficiently removed under neutral and mildly alkaline conditions. Thus, the protected ligands 7 and 13 may be used without prior removal of the protecting groups.
  • Two particularly useful steroid mimics are those that mimic the steroids cortisone and estradiol.
  • the following structures, XXVIII and XXIX represent the structure of two radionuclide complexes that will serve as cortisone and estradiol mimics:
  • the radionuclide complexes of the present invention may be used for diagnostic and therapeutic purposes.
  • the diagnostic method may be used to detect the presence or absence of a target site within an individual.
  • the method comprises the steps of administering to an individual a diagnostically effective dose of one of the radionuclide complexes described above, where the metal or metal oxide is a radionuclide and the steroid mimic is capable of binding to a steroid receptor on the target site. This step is followed by a step of detecting the biodistribution of the radionuclide in the individual to determine the presence or absence of the target site in the host.
  • the amount of the diagnostic agent according to the present invention should be sufficient to provide satisfactory imaging.
  • the dosage is generally from about 1 to about 50 mCi, and more preferrably from about 10 to about 30 mCi.
  • the diagnostic agent should be administered so as to remain in the patient for about 1 to 3 hours, although both longer and shorter time periods are acceptable. Therefore, convenient ampules containing 1 to 10 ml of aqueous solution may be prepared.
  • the precise dose for diagnostic purposes is dependent upon the particular radionuclide complex used and its affinity for its corresponding receptors.
  • the diagnostic agent may be administerd by various means including, intravenous and intratumoral administration. Preferred radionuclides are Tc-99m and Re-186.
  • the therapeutic method may be used to deliver the radionuclide complex to a target site in the individual.
  • the method comprises the step of administering to an individual a therapeutically effective dose of one of the radionuclide complexes described above, where the metal is an alpha or beta emitting metal or metal oxide and the steroid mimic is capable of binding to the target site.
  • a therapeutically effective dose is generally from about 20mCi to about 300mCi.
  • Preferred radionuclides are Re-186, Re-188, Cu-67, Rh-105, Au-198, Au-199, and Bi-212.
  • Example 1 This example illustrates the synthesis and preparation of a ligand having the structure:
  • Example 2 This example illustrates the preparation of a Tc- 99m based steroid mimic from the ligand having structure XXII described in Example 1. The formation of this radionuclide complex is also shown in Figure 1.
  • This example illustrates the preparation of a rhenium-186 based steroid mimic from the ligand having strucutre XXII described in Example 1.
  • a mixture of the ligand (200 Mg) and citric acid (50 Mg) , stannous chloride (20 Mg) and sodium perhenate solution (0.5 mL) is heated at 100° C for 15 minutes.
  • the reaction mixture is cooled to ambient temperature and the resulting solution is purified by reverse phase (C-18) HPLC to obtain the desired rhenium complex XXIII wherein M is Re.
  • This example illustrates the preparation of a rhenium-186 based steroid mimic from the ligand having the structure 10 described in Example 4.
  • This example illustrates a protocol by which ligands useful in the preparation of steroid-based radionuclide complexes may be synthesized where the metal ion is located at positions 9, 8 and 13 in the steroid skeleton structure.
  • the ligands for the preparation of radionuclide complexes having structures XV, XVI, and XVII, as described above, are shown below as structures XXV, XXVI, and XXVII:
  • ligands may be prepared as shown below by the assembly of key intermediates determined by a retrosynthetic analysis of the respective radionuclide complexes. All of the retrosynthetically derived fragments can be prepared from readily available or known starting materials and can be combined to yield the desired ligand using known reactions and reaction conditions.
  • the following compounds derived as retrosynthetic fragments of the ligand can be prepared and combined to yield the ligand:
  • 2- hydroxymethyl-4-methoxypyridine and compound 13 can be prepared from methyl 2-cyclopentanonecarboxylate and where R is selected from the group consisting of hydrogen, hydroxyl, carboxyl, amino, alkyl, aryl, alkaryl, alkaroyl, hyfroxyalkyl, hydroxyalkaroyl, alkoxy, alkoxycarbonyl and carbamoyl and where the carbon containing portions contain between 1 and 10 carbon atoms.
  • Compound 14 can be prepared from 3-methoxybenzamide and compound 15 can be prepared from proline where R is as defined above.
  • the preparation of a ligand useful in the preparation of a radionuclide complex which places the metal ion at position 13 would require the synthesis of a ligand having structure XXVII.
  • the retrosynthetic analysis of this ligand yields two fragments of which 16 is commercially available (N-acetylhomocysteine thiolactone) .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physics & Mathematics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)

Abstract

Complexes mimes stéroïdes contenant un métal, ainsi que compositions contenant un ion métallique intégré dans une structure squelettique stéroïde et ligands utiles dans la préparation desdites compositions. L'ion métallique est de préférence un radionuclide, tel que du technétium, du rhénium ou du gallium. Des procédés d'utilisation desdits complexes métalliques à des fins diagnostiques et thérapeutiques sont en outre décrits.
PCT/US1995/004338 1994-04-08 1995-04-06 Mimes steroides contenant un metal et ligands utiles dans la preparation desdits mimes Ceased WO1995027701A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP7526470A JPH09512251A (ja) 1994-04-08 1995-04-06 金属含有ステロイド模擬体およびその製造に有用なリガンド
EP95916251A EP0754177A4 (fr) 1994-04-08 1995-04-06 Mimes steroides contenant un metal et ligands utiles dans la preparation desdits mimes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/224,928 US5602236A (en) 1994-04-08 1994-04-08 Metal-containing steroid mimics and ligands useful in the preparation thereof
US08/224,928 1994-04-08

Publications (1)

Publication Number Publication Date
WO1995027701A1 true WO1995027701A1 (fr) 1995-10-19

Family

ID=22842814

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/004338 Ceased WO1995027701A1 (fr) 1994-04-08 1995-04-06 Mimes steroides contenant un metal et ligands utiles dans la preparation desdits mimes

Country Status (4)

Country Link
US (1) US5602236A (fr)
EP (1) EP0754177A4 (fr)
JP (1) JPH09512251A (fr)
WO (1) WO1995027701A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7294738B2 (en) * 2003-11-19 2007-11-13 Raghavan Rajagopalan Phosphorous containing steroid mimics
CN101626786A (zh) 2007-03-01 2010-01-13 马林克罗特公司 整合光敏肽及其应用
JP2010520238A (ja) * 2007-03-01 2010-06-10 マリンクロット インコーポレイテッド 統合された光活性低分子および統合された光活性低分子使用
WO2009018405A1 (fr) * 2007-07-31 2009-02-05 Mallinckrodt Inc. Agents photoactifs intégrés et leurs utilisations

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3492293A (en) * 1968-01-18 1970-01-27 Syntex Corp (3-keto-5-enyl steroid)palladium complexes
US4030886A (en) * 1973-12-11 1977-06-21 The Radiochemical Centre Limited Saturation analysis
US4083947A (en) * 1975-07-02 1978-04-11 The Radiochemical Centre Limited Organ visualization
US4171351A (en) * 1976-05-28 1979-10-16 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Ten Behoeve Van Nijverheid, Handel En Verkeer Telluryl compounds, their preparation and use
US4202876A (en) * 1977-01-07 1980-05-13 The Radiochemical Centre Limited Investigating body function
US4879379A (en) * 1986-09-19 1989-11-07 Yoshinori Kidani Novel platinum-steroid complexes
US4983646A (en) * 1982-09-23 1991-01-08 Centre National De La Recherche Scientifique Organometallic complexes of estrogens and their application to the determination of hormone receptors
US5330737A (en) * 1991-12-06 1994-07-19 Mallinckrodt Medical, Inc. Nitrogen-sulfur ligands as opiate receptor drug mimics

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3492293A (en) * 1968-01-18 1970-01-27 Syntex Corp (3-keto-5-enyl steroid)palladium complexes
US4030886A (en) * 1973-12-11 1977-06-21 The Radiochemical Centre Limited Saturation analysis
US4083947A (en) * 1975-07-02 1978-04-11 The Radiochemical Centre Limited Organ visualization
US4171351A (en) * 1976-05-28 1979-10-16 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Ten Behoeve Van Nijverheid, Handel En Verkeer Telluryl compounds, their preparation and use
US4202876A (en) * 1977-01-07 1980-05-13 The Radiochemical Centre Limited Investigating body function
US4983646A (en) * 1982-09-23 1991-01-08 Centre National De La Recherche Scientifique Organometallic complexes of estrogens and their application to the determination of hormone receptors
US4879379A (en) * 1986-09-19 1989-11-07 Yoshinori Kidani Novel platinum-steroid complexes
US5330737A (en) * 1991-12-06 1994-07-19 Mallinckrodt Medical, Inc. Nitrogen-sulfur ligands as opiate receptor drug mimics

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. AM. CHEM. SOC., Vol. 115, issued 1993, CHI et al., "Selective Formation of Heterodimeric Bis-Bidentate Aminothiol-Oxometal Complexes of Rhenium (V)", p. 7045-7046. *
See also references of EP0754177A4 *

Also Published As

Publication number Publication date
JPH09512251A (ja) 1997-12-09
US5602236A (en) 1997-02-11
EP0754177A1 (fr) 1997-01-22
EP0754177A4 (fr) 1997-08-27

Similar Documents

Publication Publication Date Title
CA2039218C (fr) Adduits d'acide boronique et de complexes metalliques de dioxime permettant le marquage des proteines et d'autres composes amines
CA2034042C (fr) Produits d'addition de l'acide boronique et de complexes rhenium-dioxime et technetium-99m-dioxime, contenant un groupe a activite biochimique
US5175343A (en) Metal radionuclide labeled proteins for diagnosis and therapy
US6359111B1 (en) Opioid receptor targeting
WO1996011954A1 (fr) Analogues de somatostatine radiomarques tc ou re
US6528627B1 (en) Bridged aromatic substituted amine ligands with donor atoms
US8044081B2 (en) Aminoderivative of biotin and their conjugates with macrocyclic chelating agents
US5120526A (en) Method of producing metal radionuclide labeled proteins for diagnosis and therapy
US5618513A (en) Method for preparing radiolabeled peptides
US5602236A (en) Metal-containing steroid mimics and ligands useful in the preparation thereof
US5736120A (en) Method for preparing radiolabeled peptides
US5539138A (en) High affinity chelates containing isothiocyanate groups, useful for coupling with peptides and proteins
WO1983002229A1 (fr) Glicolates de 3-quinuclidinyle a emission gamma et liant le recepteur, leur procede de preparation et procedes de mise en image et d'analyse les utilisant
WO1996011918A1 (fr) NOUVEAUX LIGANDS CHELATEURS DE TYPE N3S2 EVENTUELLEMENT RADIOMARQUES A L'AIDE DE Tc OU Re ET DESTINES A ETRE UTILISES DANS DES APPLICATIONS DIAGNOSTIQUES OU THERAPEUTIQUES
WO1997010854A1 (fr) Composes de biotine (radio) marques
TWI381852B (zh) 生物素二胺基衍生物類及其與大環螯合劑之共軛物
US6143275A (en) Type S3 N2 chelators for radioactive isotopes, their metal complexes and their diagnostic and therapeutical use
CA2031528C (fr) Composes metalliques chelatants radioactifs pour le marquage des proteines
Stahl et al. Technetium-99m-labeled HOE 140: a potential bradykinin B2 receptor imaging agent
CA2173844A1 (fr) Chelateurs n-alkylpeptidiques, leurs complexes metalliques avec des radionucleides, procedes pour leur preparation et compositions radiopharmaceutiques contenant ces composes
US6534037B1 (en) Non-steroidal compounds for steroid receptors and uses relating thereto
JP2006514612A (ja) 固体支持体からの金属補助切断を介する固相技法によるｍ（ｃｏ）３錯体の製造
EP0757694A1 (fr) Composes thioether destines a la preparation d'agents chelateurs bifonctionnels pour des produits radiopharmaceutiques therapeutiques

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1995916251

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1995916251

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1995916251

Country of ref document: EP